Somatostatin analogues

Abstract

The polypeptides, ##STR1## the linear precursor intermediates therefor or non-toxic acid addition salts thereof in which X 2 is NH 2 , Ala-Gly-, Ala-D-Ala-, Gly-Gly-Gly-, lower alkanoyl or benzoyl; X 4 is Arg, His, D-Arg or D-His; X 5 is His, Tyr, Glu, D-His, D-Tyr or D-Glu; X 7 is Trp, Tyr, Met or His; and X 8 is Trp or D-Trp; inhibit the release of growth hormone and are useful in the treatment of acromegaly and diabetes.

What is claimed is: 
     
       1. A compound of the formula:   R-[Y.sub.2 ].sub.n -Cys(R.sup.1)-X.sub.4 (R.sup.2)-X.sub.5 (R.sup.3)-Phe-X.sub.7 (R.sup.4)-X.sub.8 -Lys(R.sup.5)-Thr(R.sup.6)-Phe-Thr(R.sup.7)-Ser(R.sup.8)-Cys(R.sup.9)-O-CH.sub.2 [polystyrene resin support]     in which   R is hydrogen, an α-amino protecting group, lower alkanoyl or benzoyl;   R 1  and R 9  are a thio protecting group;   R 2  is a protecting group for N g  of Arg, or the N im  of His;   R 3  is a protecting group for N im  of His or the hydroxyl group of Tyr;   R 4  is a protecting group for the 1H indole nitrogen of Trp, the N im  of His, or the hydroxyl group of Tyr;   R 5  is an amino protecting group;   R 6  is a hydroxyl protecting group for Thr;   R 7  and R 8  are a hydroxyl protecting group for Thr and Ser; where     Y 2  is Ala-Gly, Ala-D-Ala- or Gly-Gly-Gly;   n is 0 or 1;   X 4  is Arg, His, D-Arg, or D-His;   X 5  is His, Tyr, Glu, D-His, D-Tyr, or D-Glu;   X 7  is Trp, Tyr, Met, or His; and     X 8  is Trp or D-Trp.   
     
     
       2. 
     
     
       The compound of claim 1 which is tert-butyloxycarbonyl-S-p-methoxybenzyl-L-cysteinyl-N g  -tosyl-L-arginyl-N im  -tosyl-L-histidyl-L-phenylalanyl-L-tryptophyl-D-tryptophyl-N.sup.ε -2-chlorobenzyloxycarbonyl-L-lysyl-O-benzyl-L-threonyl-L-phenylalanyl-O-benzyl-L-threonyl-O-benzyl-L-seryl-S-p-methoxybenzyl-L-cysteinyl hydroxymethyl polystyrene ester. 
     
     
       3. The compound of claim 1 which is tert-butyloxycarbonyl-S-p-methoxybenzyl-L-cysteinyl-N g  -tosyl-L-arginyl-N im  -tosyl-L-histidyl-L-phenylalanyl-N im  -tosyl-L-histidyl-D-tryptophyl-N.sup.ε -2-chlorobenzyloxycarbonyl-L-lysyl-O-benzyl-L-threonyl-L-phenylalanyl-O-benzyl-L-threonyl-O-benzyl-L-seryl-S-p-methoxybenzyl-L-cysteinyl hydroxymethyl polystyrene ester.